MerTK + macrophages promote melanoma progression and immunotherapy resistance through AhR-ALKAL1 activation.

Autor: Wu N; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.; Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China., Li J; Department of Dermatology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China., Li L; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.; Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China., Yang L; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.; Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China., Dong L; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.; Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China., Shen C; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.; Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China., Sha S; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.; Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China., Fu Y; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.; Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China., Dong E; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.; Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China., Zheng F; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China., Tan Z; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China., Tao J; Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.; Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Oct 04; Vol. 10 (40), pp. eado8366. Date of Electronic Publication: 2024 Oct 04.
DOI: 10.1126/sciadv.ado8366
Abstrakt: Despite our increasing understanding of macrophage heterogeneity, drivers of macrophage phenotypic and functional polarization in the microenvironment are not fully elucidated. Here, our single-cell RNA sequencing data identify a subpopulation of macrophages expressing high levels of the phagocytic receptor MER proto-oncogene tyrosine kinase (MerTK + macrophages), which is closely associated with melanoma progression and immunotherapy resistance. Adoptive transfer of the MerTK + macrophages into recipient mice notably accelerated tumor growth regardless of macrophage depletion. Mechanistic studies further revealed that ALK And LTK Ligand 1 (ALKAL1), a target gene of aryl hydrocarbon receptor (AhR), facilitated MerTK phosphorylation, resulting in heightened phagocytic activity of MerTK + macrophages and their subsequent polarization toward an immunosuppressive phenotype. Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti-programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK + macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.
Databáze: MEDLINE
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